Platelet ultrastructural abnormalities in three patients with type 2B von Willebrand disease

Montreal platelet syndrome (MPS), hitherto described in only one kindred, is a hereditary thrombocytopenia associated with mucocutaneous bleeding, giant platelets, and spontaneous platelet aggregation in vitro. These are features shared with some forms of type 2B von Willebrand disease (VWD); however, the MPS kindred had not been investigated for VWD. We found that all affected MPS family members had borderline to normal von Willebrand factor antigen (VWF:Ag; 0.43-0.75 U/mL), discrepantly low ristocetin cofactor activity (VWF:RCo; 0.16-0.29 U/mL), and normal factor VIII coagulant activity (FVIII:C; 0.57-1.04 U/mL). Unaffected family members all had normal VWF:Ag, VWF:RCo, and FVIII:C levels. In addition, persons with MPS, but not unaffected family members, had loss of plasma (but not platelet) high molecular weight VWF multimers, and were heterozygous for the previously reported V1316M type 2B VWD mutation. Thus, in reevaluating this kindred, we determined that patients with MPS have type 2B VWD with the V1316M VWF mutation. (Blood. 2009;113:3348-3351)

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation

Jackson

Sinclair

Cloutier

et al. 2009

“…15,16 Nurden et al also evaluated platelet morphology by electron microscopy in VWD2B patients and found some ultrastructural abnormalities. 36 Another aim of this study was to confirm in a large series of patients the clinical significance of the measurement of VWFGPIb-␣/BC. In addition to the few cases with VWD2B and thrombotic thrombocytopenic purpura originally reported, 26 the VWF-GPIb-␣/BC was investigated only in another study on the effect of exercise on VWF.…”

Section: Discussionmentioning

confidence: 99%

Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients

Federici

Mannucci

Castaman

et al. 2009

243

308

Type 2B von Willebrand disease (VWD2B)is caused by an abnormal von Willebrand factor (VWF) with increased affinity for the platelet receptor glycoprotein Ib-␣ (GPIb-␣) that may result in moderate to severe thrombocytopenia. We evaluated the prevalence and clinical and molecular predictors of thrombocytopenia in a cohort of 67 VWD2B patients from 38 unrelated families characterized by VWF mutations. Platelet count, mean platelet volume, and morphologic evaluations of blood smear were obtained at baseline and during physiologic (pregnancy) or pathologic (infections, surgeries) stress conditions. Thrombocytopenia was found in 20 patients (30%) at baseline and in 38 (57%) after stress conditions, whereas platelet counts were always normal in 16 patients (24%) from 5 families carrying the P1266L/Q or R1308L mutations. VWF in its GPIb-␣-binding conformation (VWFGPIb-␣/BC) was higher than normal in all except the 16 cases without thrombocytopenia (values up to 6-fold higher than controls). The risk of bleeding was higher in patients with thrombocytopenia (adjusted hazard ratio ‫؍‬ 4.57; 95% confidence interval, 1.17-17.90) and in those with the highest tertile of bleeding severity score (5.66; 95% confidence interval, 1.03-31.07). Prediction of possible thrombocytopenia in VWD2B by measuring VWF-GPIb-␣/BC is important because a low platelet count is an independent risk factor for bleeding. (Blood. 2009;113: 526-534)

“…Platelets were kept in 0.2% glutaraldehyde at 4°C until processing for standard electron microscopy, as previously described. 23 …”

Section: Electron Microscopymentioning

confidence: 99%

Platelet JNK1 is involved in secretion and thrombus formation

Adam

Kauskot

Nurden

et al. 2010

Self Cite

104

106

The role of c-Jun NH 2 -terminal kinase 1 (JNK1) in hemostasis and thrombosis remains unclear. We show here, with JNK1-deficient (JNK1 ؊/؊ ) mice, that JNK1 plays an important role in platelet biology and thrombus formation. In tail-bleeding assays, JNK1 ؊/؊ mice exhibited longer bleeding times than wild-type mice (396 ؎ 39 seconds vs 245 ؎ 32 seconds). We also carried out in vitro whole-blood perfusion assays on a collagen matrix under arterial shear conditions. Thrombus formation was significantly reduced for JNK1 ؊/؊ platelets (51%). In an in vivo model of thrombosis induced by photochemical injury to cecum vessels, occlusion times were 4.3 times longer in JNK1 ؊/؊ arterioles than in wild-type arterioles. Moreover, in vitro studies carried out in platelet aggregation conditions demonstrated that, at low doses of agonists, platelet secretion was impaired in JNK1 ؊/؊ platelets, leading to altered integrin ␣IIb␤3 activation and reduced platelet aggregation, via a mechanism involving protein kinase C. JNK1 thus appears to be essential for platelet secretion in vitro, consistent with its role in thrombus growth in vivo. Finally, we showed that ERK2 and another isoform of JNK affect platelet aggregation through 2 pathways, one dependent and another independent of JNK1.